Degradable thiol-ene polymers

ABSTRACT

A thiol-ene polymeric material is disclosed. The material is produced by the photopolymerization of reactants having thiol and olefin moieties. The material can incorporate encapsulated components, including cells. Additionally, the material can be derivatized by reacting the polymeric material with components such as proteins.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.11/858,062, filed Sep. 19, 2007, which is a divisional of U.S. patentapplication Ser. No. 10/269,916, filed Oct. 10, 2002, which claimspriority under 35 U.S.C. §119(e) from U.S. Provisional Application Ser.No. 60/328,669, filed Oct. 10, 2001, all of which are incorporatedherein by reference in their entirety.

STATEMENT REGARDING FEDERALLY FUNDED RESEARCH

The U.S. Government has a paid-up license in this invention and theright in limited circumstances to require the patent owner to licenseothers on reasonable terms as provided for by the terms of Grant No. CTS945-3369 awarded by the National Science Foundation.

FIELD OF THE INVENTION

The invention is directed to the production of degradable thiol-enebased polymers via photopolymerization.

BACKGROUND OF THE INVENTION

Recent approaches in the field of tissue engineering involve the use ofpolymeric biomaterials as cell scaffolds, which provide cells with athree-dimensional support material on which to grow. Despite a recentexpansion in the design and development of suitable scaffold materials,there is still a lack of suitable scaffold materials with systematicallyvariable properties. Without suitable materials available with a widerange of properties to serve as scaffolds for tissue engineering, it isunlikely that the field will achieve its full potential.

Advances in polymer chemistry and materials science have spawned thedevelopment of numerous biomaterials and scaffolding methods that havepotential uses in a wide range of tissue engineering applications.Several criteria must be achieved in the design of a biomaterial. First,the material must be biocompatible. That is, it must not promote animmune, allergenic, or inflammatory response in the body. Also, a methodmust exist to reproducibly process the material into a three-dimensionalstructure. Adhesive properties of the surface of the biomaterial mustpermit cell adhesion and promote growth. In addition, the biomaterialshould have a high porosity to facilitate cell-polymer interactions,improve transport properties, and provide sufficient space forextracellular matrix generation. Finally, depending upon the particularapplication, the biomaterial should be biodegradable with an adjustabledegradation rate so that the rate of tissue regeneration and the rate ofscaffold degradation can be matched.

Natural materials, such as collagen and many polysaccharides, generallyexhibit a limited range of physical properties, are difficult toisolate, and cannot be manufactured with a high degree ofreproducibility. However, natural materials often are more biocompatibleand may even have specific biologic activity. Synthetic materials, onthe other hand, can be cheaply and reproducibly processed into a varietyof structures and the mechanical strength, hydrophilicity, anddegradation rates of synthetic scaffolds are more readily tailored.However, synthetic polymers can cause inflammatory responses whenimplanted in the host. Recent tissue engineering endeavors haveattempted to combine properties of both natural and synthetic polymersin the design of a suitable scaffold.

Polylactide (PLA), polyglycolide (PGA) and their copolymers (PLGA) arepolyesters based on naturally occurring lactic and glycolic acids(α-hydroxy acids). They have been used as biodegradable sutures andimplantable materials for more than two decades. They are biocompatibleand biodegradable, and these polymers have a history of use as polymerscaffolds in tissue engineering. However, their highly crystalline andhydrophobic nature makes it difficult to control their biodegradationprocess and mechanical properties. Moreover, because of the lack ofpendant functional groups, it is extremely difficult to modify thesurface chemistry of PLA and PGA. For example, proteins and othermolecules that may facilitate cell adhesion and growth cannot be easilyattached to the backbone of these polymers because there is no chemical“handle” with which to derivatize these substrates. Attempts tointroduce functional groups into these types of polymers includecopolymerization of the lactide and glycolide cyclic monomers with moreeasily derivatizable monomers such as cyclic lysine monomers modified bypeptide attachments.

Recently, alternating copolymers of α-hydroxy acids and α-amino acids(polydepsipeptides) have been obtained with functional side groups.Additionally, poly(L-lactides) containing β-alkyl α-malate units havebeen prepared by ring opening copolymerization of L-lactide with acyclic diester. Major drawbacks remain with these lactide basedcopolymers including the difficulty in synthesis of cyclic monomers thatare used in the copolymerization with lactide and the generally lowreaction yields. Thus, the difficult synthesis and the low reactionyields make the commercialization of the modified polylactidebiomaterials improbable and make it nearly impossible to tailorchemical, physical, and degradation properties of the final polymer.

Photopolymerization systems have numerous advantages for matrixproduction. First, photoinitiation allows facile control over thepolymerization process with both spatial and temporal control. Forexample, a liquid macromer solution can be injected into an area of thebody, formed into a particular shape, and photopolymerized on demandusing a light source. The final polymer hydrogel maintains the shape ofthat specific area of the body, allowing intimate control over the finalshape of the hydrogel and improved adhesion and integration. Inaddition, the photocrosslinking chemistry creates covalently crosslinkednetworks that are dimensionally stable.

Known photopolymerization processes, however, suffer from a number ofdrawbacks, including: the use of a separate initiator specie that iscytotoxic at relatively low concentrations, the difficulty inpolymerizing thick samples because of light attenuation by theinitiator, the inhibition of the radical polymerization by oxygenpresent in the air (which slows the polymerization), and the ability tofabricate gels with a diverse range of properties, especially gels witha high water content while maintaining high mechanical strength. Thus,there exists a need for biocompatible hydrogels which can polymerize inthe absence of cytotoxic initiators and which can be tailored to havespecific chemical, physical, and degradation properties underphysiological conditions.

SUMMARY OF THE INVENTION

One embodiment of the present invention is a polymeric material havingrepeating units of the formula: —[—S—R₁—S—C—C—R₂—C—C—]—, wherein R₁ andR₂ are independent linkers, and at least one of R₁ and R₂ aredegradable. R₁ and R₂ can be independently selected from poly(lacticacid), poly(ethylene glycol), poly(vinyl alcohol), and mixtures thereof,and one or both of R₁ and R₂ can have a degree of branching of greaterthan two. The polymeric material is preferably biocompatible, and canhave a minimum dimension of at least about 4 cm.

The polymeric materials of the present invention can be produced by aprocess that includes combining a first reactant of the formulaR₁B(C═C)_(n) with a second reactant of the formula R₂B(SH)_(m), whereinn and m are independently integers greater than one and R₁ and R₂ are asdescribed above. The combined reactants are then irradiated with lightto cause reaction between the first and second reactants and eventuallybetween the formed products to obtain the polymeric material. Thisprocess can include irradiating the reactants in the absence of achemical initiator.

In a further embodiment, the polymeric material can include at least onebiologically active component encapsulated within it. The biologicallyactive component can be selected from the group consisting of cells,tissues, and tissue aggregates, such as chondrocytes, immortalized celllines, stem cells, hormone-producing cells, or fibroblasts.Additionally, the biologically active component can includepharmacologically active agents or agricultural chemicals.Pharmacologically active agent functional molecules can includeanalgesics, antipyretics, nonsteroidal antiinflammatory drugs,antiallergics, antibacterial drugs, antianaemia drugs, cytotoxic drugs,antihypertensive drugs, dermatological drugs, psychotherapeutic drugs,vitamins, minerals, anorexiants, dietetics, antiadiposity drugs,carbohydrate metabolism drugs, protein metabolism drugs, thyroid drugs,antithyroid drugs, or coenzymes. Agricultural chemical functionalmolecules can include fungicides, herbicides, fertilizers, pesticides,carbohydrates, nucleic acids, organic molecules, or inorganicbiologically active molecules.

In another embodiment, the polymeric material can be derivatized with afunctional molecule, for example, by forming the polymeric material withexcess thiol groups and reacting the functional molecule with suchexcess thiol groups. The functional molecules can be, for example,proteins, agricultural chemicals, or pharmacologically active agents.Protein functional molecules can include adhesion peptides, growthfactors, hormones, antihormones, signaling compounds, serum proteins,albumins, macroglobulins, globulins, agglutinins, lectins, antibodies,antigens, enzymes, or extracellular matrix proteins. The polymericmaterial of the present invention can also be configured to form adegradable commodity plastic.

A further embodiment of the present invention includes a thiol-enehydrogel having poly(lactic acid), poly(ethylene glycol), and poly(vinylalcohol) polymeric segments, wherein at least one of the segments has adegree of branching of greater than two. In this embodiment, thethiol-ene hydrogel has a modification selected from encapsulation of atleast one biologically active component within the thiol-ene hydrogeland derivatization of the thiol-ene hydrogel with a functional molecule.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the general scheme for thiol-ene polymerization.

FIG. 2 shows a scheme for the formation of a thiol-ene hydrogel formedfrom derivatized PLA, PEG and PVA monomers.

FIG. 3 shows schemes for derivatizations of poly(vinyl alcohol).

FIG. 4 shows schemes for derivatizations of poly(lactic acid).

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a novel class of degradablescaffolds which are biocompatible thiol-ene hydrogels built upondegradable materials, such as PVA, PEG and PLA blocks, that canincorporate chemicals and live cells within the polymer matrix.

Thiol-ene polymerizations are photochemically initiated, step growth,free-radical processes that take place between thiols and olefins via asequential propagation/chain-transfer process. For polymerization tooccur, each thiol-containing component must have an average of at leasttwo thiol groups and each olefin-containing component must have at leasttwo ene functional groups, (i.e. the monomer must contain two or moredouble bonds). Polymerization of a dithiol and a diene results in theformation of a linear polymer, rather than a crosslinked polymer.Crosslinked gels can be readily formed by increasing the functionality,i.e., increasing the degree of branching, of one or both of the monomersto be greater than two. Thiol-ene polymerizations have a number ofsignificant and unique advantages that make them particularlybeneficial. These benefits include a step growth polymerization thatcauses the molecular weight to build up more slowly, the ability tophotoinitiate the sample without any need for a distinct (and possiblycytotoxic) initiator specie, the ability to polymerize extremely thick(more than 30 cm) samples because of a self-eliminating light intensitygradient, the very low radical concentration present duringpolymerizations producing less cellular damage from the free radicals,the lack of oxygen inhibition and the ease with which monomers ofsignificantly varying chemistry can be copolymerized.

Thiol-ene systems form ground state charge transfer complexes, andtherefore photopolymerize even in the absence of initiators inreasonable polymerization times. Since the complex which absorbs thelight is consumed by the polymerization, the polymer itself does notabsorb light. Thus, polymerization can proceed to extremely greatdepths, and no potentially toxic initiator is required to initiate thepolymerization. The polymer properties can be tailored by appropriatemonomer choices since the products are regular, alternating copolymers.Nearly any unsaturated monomer can polymerize via this mechanism in thepresence of a suitable polythiol and light.

The scheme shown in FIG. 1 is the general polymerization mechanism. Thecharge transfer complex forms by the interaction of the thiol group withthe double bond of the ene followed by electron transfer and formationof a thiyl radical upon exposure to light. The thiyl radical theninitiates the polymerization. Termination involves radical-radicalcombinations of either β-carbon radicals or thiyl radicals.

One embodiment of the present invention is a polymeric materialcomprising repeating units of the formula:

—[—S—R₁—S—C—C—R₂—C—C—]—

wherein R₁ and R₂ are independent linkers, and at least one of R₁ and R₂are degradable. Thus, the chemical natures of R₁ and R₂ are independent,that is, they can be the same or different. R₁ and R₂ function aslinkers to link together the thiol-ene junctures. In accordance with thepresent invention, the polymeric material is preferably produced by aprocess of combining a first reactant of the formula R₁—(C═C)_(n) with asecond reactant of the formula R₂—(SH)_(m), wherein n and m areindependently integers greater than one and R₁ and R₂ are as definedabove. The first and second reactants are then irradiated with light tocause reaction between the first and second reactants to form thepolymeric material. In alternative embodiments, the polymeric materialof the present invention can include additional linker segments, R₃ . .. R_(n). Such additional linker segments meet the requirements set forthherein for R₁ and R₂. For example, a polymeric material having therepeating unit described above can further comprise repeating units ofthe formula:

—[—S—R₃—S—C—C—R₄—C—C-]—

wherein R₃ and R₄ are independent linkers.

As used herein, the term “degradable,” with reference to the R₁ and R₂segments and the polymeric materials of the present invention refers toa segment or material having a molecular structure which can decomposeto smaller molecules. Such degradation or decomposition can be byvarious chemical mechanisms. For example, a degradable polymer can behydrolytically degradable in which water reacts with the polymer to formtwo or more molecules from the polymer by chemical bonds in the moleculebeing hydrolyzed, thus producing smaller molecules. In a furtherembodiment of the present invention, the segments or materials arebiodegradable. Biodegradability refers to a compound which is subject toenzymatic decomposition, such as by microorganisms, or to a compound,portions of which are subject to enzymatic decomposition, such as bymicroorganisms.

R₁ and R₂, while at least one is degradable, can be chemically diverse.In preferred embodiments, R₁ and R₂ can be selected from poly(lacticacid) (PLA), polyglycolide (PGA), copolymers of PLA and PGA (PLGA),poly(vinyl alcohol) (PVA), poly(ethylene glycol) (PEG), poly(ethyleneoxide), poly(ethylene oxide)-co-poly(propylene oxide) block copolymers(poloxamers, meroxapols), poloxamines, polyanhydrides, polyorthoesters,poly(hydroxy acids), polydioxanones, polycarbonates,polyaminocarbonates, poly(vinyl pyrrolidone), poly(ethyl oxazoline),carboxymethyl cellulose, hydroxyalkylated celluloses such ashydroxyethyl cellulose and methylhydroxypropyl cellulose, and naturalpolymers such as polypeptides, polysaccharides or carbohydrates such aspolysucrose, hyaluronic acid, dextran and similar derivatives thereof,heparan sulfate, chondroitin sulfate, heparin, or alginate, and proteinssuch as gelatin, collagen, albumin, or ovalbumin, or copolymers, orblends thereof. In particularly preferred embodiments, R₁ and R₂ can beselected from poly(lactic acid) (PLA), poly(vinyl alcohol) (PVA), andpoly(ethylene glycol) (PEG). PLA monomers provide degradability to thesystem while PVA and PEG enhance the hydrophilic nature of the hydrogeland provide for the possibility of further derivatization and/orextensive crosslinking.

R₁ and R₂ can vary in size depending upon desired properties for theresulting polymeric material. More particularly, the molecular weightfor R₁ and R₂ can range from about 30 DA to about 50000 Da. Prior toformation of the polymeric material of the present invention, R₁ and R₂are derivatized to include thiol or olefin moieties such that they canparticipate in photo-initiated thiol-ene polymerization. Thiolatedmacromers such as poly(ethylene glycol) dithiol are availablecommercially. The olefin moieties can be selected from any suitablecompound having a carbon double bond. For example, the olefin moiety canbe selected from any suitable ethylenically unsaturated group such asvinyl, acetyl, vinyl ether, allyl, acrylate, methacrylate, maleimide,and norbornene. Thus, it will be appreciated that in the repeating unitshown above, the carbons can be CH₂ or can be substituted at one or morethan one of the carbons within the repeating group, even including ringstructures incorporating a double bond. If each of R₁ and R₂ arederivatized with either two thiol or two olefin moieties, the resultingthiol-ene polymer would be a linear copolymer composed of alternating R₁and R₂ segments. However, the thiol-ene polymeric material is preferablyformed to contain cross-linking and branching. Thus, the derivatized R₁and R₂ segments preferably have more than two thiol or olefin moietiesper molecule that can participate in crosslinking and polymerization.The extent of the branching and crosslinking can be controlled by theuse of differently derivatized R₁ and R₂ segments and control over theconcentration of the starting materials.

By photoinitiation of the thiol-ene polymerization reaction with thesemonomeric, oligomeric or polymeric starting materials, high molecularweight, crosslinked networks are obtainable in the presence or absenceof a chemical initiator within reasonable reaction times. This is a veryimportant property inherent to the polymerization reactions, which caneliminate the adverse effects of chemical initiators and still obtainrapid curing. Because of the step growth nature of the polymerization,these polymers have significantly lower glass transition temperaturesand higher degrees of swelling than homopolymer diacrylate analogues.Thus, simple changes in molecular weight, number of functional groups,and the chemistry of the monomer between the functional groups allowfacile control of the polymer properties over a wide range.

FIG. 2 illustrates an example of a thiol-ene hydrogel that can be formedfrom derivatized PLA, PEG and PVA monomers. The resulting hydrogel isformed from the PLA triene (e.g., made from glycerol with three lactidearms and subsequent ene attachment), the PEG dithiol (such as thecommercially available PEG dithiol), and the partially acrylated PVAderivatized to include the well-known RGD adhesion sequence. Hydrogelmatrices of this type facilitate independent control of the (i)mechanical properties by adjusting the PVA and PLA functionality, (ii)swelling through adjustments to the relative amount of PEG, (iii) thedegradation timescale through adjustments in the molecular weight of thePLA arms, and (iv) attachment of biomolecules such as signalingcompounds to the PVA backbone. The resulting networks will be threedimensional, hydrophilic, porous structures that can be further modifiedby the attachment of molecules of interest to the pendant —OH groups ofPVA to impart therapeutic or other properties to the hydrogel. Thiol-enepolymers are alternating copolymers, but because a monomer can bederivatized in numerous ways, the ability to vary the composition of thecopolymers exists.

A list of some properties of the thiol-ene hydrogel illustrated in FIG.2 that can be influenced by modifying parameters of the individualmonomers is shown in Table 1. Degradation rate, mechanical properties,crosslink density and swelling can each be controlled with systematicchanges in the amounts, molecular weights or functionality of thevarious monomers. For example, in considering control of the degradationrate of the polymer matrix, the simplest method for controlling thisfeature is to change the molecular weight of the oligomeric PLAbranches. The higher the molecular weight of the branch, the morerapidly the system will degrade. This phenomena, which is different fromwhat might be observed in linear PLA systems, arises because the PLAsegments may act as crosslinks in the system. As the molecular weight ofthe PLA crosslink increases, the probability that any one of the repeatunits and hence the crosslink will be degraded is higher, thus leadingto more rapid degradation of the PLA crosslinks.

TABLE 1 Influence of Monomer Amounts and Structural Features on thePolymer Matrix Properties Monomer Parameters to be Varied PrimaryInfluence Secondary Influence Molecular Weight of Degradation RateSwelling (minor) PLA Branches Number of PLA Crosslink Density SwellingBranches per Mechanical Properties PLA Monomer (i.e., the functionality)Amount of PLA Crosslink Density Swelling (minor) Monomer MechanicalProperties Degree of Substitution Crosslink Density Swelling - alsochanges on PVA Backbone Mechanical Properties because of consumption ofhydrophilic —OH functional groups Amount of PEG Swelling CrosslinkDensity Monomer (minor)

Another parameter that dictates the network properties is monomerfunctionality. For example, in the example shown in FIG. 2, as thenumber of reactive functional groups on the PLA branched oligomer or PVAincreases, the extent of crosslinking increases, giving more rigidhydrogels. Increasing the functionality of the PVA monomers requiresconsuming additional —OH functional groups and converting them to thiolsor vinyl substituents. The loss of hydroxyl functional groups reducesthe network hydrophilicity to a minor degree, thus impacting theswelling. Additionally, for both of these changes, the increase incrosslink density impacts the initial equilibrium swelling; however, theswelling is more easily controlled by the amount of PEG added to thematrix. The functionality of the PLA will be adjusted by starting withdi-, tri-, and tetra-functional alcohols in the PLA synthesis to obtaindi-, tri- and tetra-functional oligomers (i.e. oligomers with two, threeand four branches). The size of the oligomer chains is controlled duringthe synthesis by changing the ratio of hydroxyl groups to lactides. ThePVA functionality can be manipulated by replacing between about 2% andabout 10% of the hydroxyl functional groups with vinyl or thiol groups.

As noted above, the thiol-ene hydrogels of the present invention areprepared from biocompatible monomers. A biocompatible material does notpromote an immune, allergenic or inflammatory response in the body. Theresulting hydrogels are therefore biocompatible as well and can be usedinternally for the purposes of tissue engineering. Because theindividual monomers are biocompatible and the polymerization processitself can be free of toxic chemical initiators, it is also possible toencapsulate biologically active materials, such as cells, tissue andtissue aggregates during the polymerization process thereby trappingsuch materials within the biocompatible hydrogel matrix. These materialsare then supported within the matrix and can function within the correcttemperature, water and nutrient environment. Cells of interest forencapsulation include chondrocytes, immortalized cell lines, stem cells,hormone-producing cells, fibroblasts and the like. To have an optimalcell environment, the hydrophilicity and transport properties (e.g.diffusion) must be controlled. In particular, the matrices must allowfor the ready transport of nutrients and oxygen to encapsulated cells,as well as the removal of cellular waste products. Suitable matricesinclude multi-branched PLA and PVA chains either linked to each other orto PEG segments to form a three dimensional structure. PEG is extremelyhydrophilic. Therefore, the presence of large amounts of PEG (as well asthe remaining hydroxyls from the PVA) assure that the degree of swellingof the hydrogel is high and that transport is facile.

In a further embodiment of the present invention, monomers aresynthesized that contain chemical links to allow for derivatization ofthe polymeric material with functional molecules as well as thenecessary thiol and olefin moieties for formation of the hydrogel. Forexample, the monomers could be derivatized to contain multiple thiolgroups, some of which are derivatized to link a protein while others areleft free to participate in the thiol-ene polymerization thereby forminga thiol-ene hydrogel containing bound protein. Alternatively, athiol-ene hydrogel can be produced with monomers having an excess ofthiol groups and after formation, the hydrogel can be derivatized with aprotein.

Knowledge of the biological events that occur at the cell-scaffoldinterface plays a key role in tissue engineering. Vital interactionsoccur on the molecular scale, and the proteins and factors that areresponsible for these interactions may be incorporated into suitablescaffolding materials by derivatization of the polymeric material of thepresent invention. For example, signaling molecules, hormones, andgrowth factors each can be integrated into the hydrogel throughderivatization of the monomers, macromers or polymers, thereby mimickingthe native environment (i.e., in the body) of those cells, resulting inmore efficient production of extracellular matrix and improvedtissue-like properties of the final material. One of the significantadvantages of the thiol-ene approach is the simplicity with which theresulting polymeric networks can be derivatized. The thiols can beeasily modified either before or after polymerization (if a slightexcess of thiol is added to the polymerization, a significant number ofthiols will remain unreacted and derivatizable).

A wide variety of molecules can be incorporated into the polymericmaterial through —OH groups or —SH groups including, but not limited to,proteins, pharmacologically active agents, and agricultural chemicals.Alternatively, such molecules can be encapsulated in the polymericmaterial in the event such molecules would lose functionality ifchemically bound to the polymeric material. For example, types ofproteins that can be incorporated into the polymeric material includeadhesion peptides (such as RGD adhesion sequence), growth factors,hormones, antihormones, signaling compounds, enzymes, serum proteins,albumins, macroglobulins, globulins, agglutinins, lectins, extracellularmatrix proteins, antibodies, and antigens. Types of pharmacologicallyactive agents that can be incorporated into the polymeric materialinclude analgesics, antipyretics, nonsteroidal antiinflammatory drugs,antiallergics, antibacterial drugs, antianemia drugs, cytotoxic drugs,antihypertensive drugs, dermatological drugs, psychotherapeutic drugs,vitamins, minerals, anorexiants, dietetics, antiadiposity drugs,carbohydrate metabolism drugs, protein metabolism drugs, thyroid drugs,antithyroid drugs, and coenzymes. Types of agricultural chemicals thatcan be incorporated into the polymeric material include fungicides,herbicides, fertilizers, pesticides, carbohydrates, nucleic acids,organic molecules, and inorganic biologically active molecules. In afurther embodiment, the polymeric material of the present invention canbe formed as commodity plastic products that are typically considered tobe disposable products. Because the polymeric material of the presentinvention is degradable, such products, when disposed of, will morerapidly degrade in the environment. Such products include, for example,eating utensils, plates, bowls, cups, food and beverage containers andpackaging.

The following experimental results are provided for purposes ofillustration and are not intended to limit the scope of the invention.

EXAMPLES Example 1

This example shows two possible derivatizations of poly(vinyl alcohol).

Synthesis of a thiol macromer can proceed via several approaches, two ofwhich are presented in the scheme shown in FIG. 3. Both progress via atosylate intermediate. Poly(vinyl alcohol) was tosylated in anhydrouspyridine at 85° C. overnight. The insoluble PVA was pulled into solutionas the reaction proceeded. This tosylated PVA was then be reacted withdithiothreitol (DTT), in one instance, and potassium thioacetate, inanother instance, at room temperature. Nucleophilic attack of thethiolate anion displaced the tosyl group, covalently linking thesemolecules to the PVA backbone through a thioether bond. PVA-thioacetatewas hydrolyzed via simple methanolysis, yielding the thiol macromer(PVA-SH) in which the thiol groups have replaced some of the hydroxylgroups. Using an excess of DTT in the other mechanism guarantees thatthere will be free thiol groups in the resulting molecule (PVA-DTT).

Once formed, the thiolated PVA can then be photopolymerized in thepresence of a multi-ene in an aqueous solution to provide a crosslinkedhydrogel network. Polymerizations of the thiolated PVA with the PLAtriacrylate or PLA triallyl yield a degradable, hydrogel network inwhich the swelling and degradation time are controlled by the amount andmolecular weight of the trifunctional PLA, respectively.

Example 2

This example demonstrates the feasibility of synthesizing PLA multi-eneand PLA multithiol monomers for use in the present invention.

A major advantage of thiol-ene hydrogels is the ability to use a widerange of precursor molecules with varying structures and chemistries. Inparticular, the technique affords the possibility of having largelypoly(lactic acid) polymers in which the degradation rate is controlledby the PLA segment molecular weight. To obtain this control, it isnecessary to synthesize PLA multi-enes and PLA multithiols. FIG. 4 showsthe scheme for the synthesis of PLA trithiol and PLA triacrylate.

Lactic acid oligomers with three branches were prepared with glycerolused as an initiator to polymerize the lactide using stannous octoate asthe catalyst. Oligomers with different chain lengths were obtained byadjusting the initiator/lactide ratio. This oligomer was used toderivatize the hydroxyl end groups of the three branches either withacrylates or with thiols. None of the PLA thiol derivatives havepreviously been synthesized. Synthesized macromers were characterized byFTIR and NMR. PLA triacrylate showed all the reported IR and ¹H-NMRbands.

While various embodiments of the present invention have been describedin detail, it is apparent that modifications and adaptations of thoseembodiments will occur to those skilled in the art. It is to beexpressly understood, however, that such modifications and adaptationsare within the scope of the present invention, as set forth in theclaims below.

1. A method for producing a biocompatible cross-linked degradablethiol-ene hydrogel polymer comprising subjecting a polymerizationreaction mixture comprising a thiol compound and an olefin compound to aradical polymerization reaction under conditions sufficient to produce abiocompatible cross-linked degradable thiol-ene hydrogel polymer,wherein the thiol compound comprises m number of reactive thiol groups,and the olefin compound comprises n number of reactive ene groups, andwherein each of n and m is an integer of at least 2, provided the sum ofn+m is at least
 5. 2. The method of claim 1, wherein the thiol compoundcomprises a polymeric moiety selected from the group consisting ofpoly(lactic acid) (PLA); polyglycolide (PGA); a copolymer of PLA and PGA(PLGA); poly(vinyl alcohol) (PVA); poly(ethylene glycol) (PEG);poly(ethylene oxide); a poly(ethylene oxide)-co-poly(propylene oxide)block copolymer; a poloxamine; a polyanhydride; a polyorthoester; apoly(hydroxy acids); a polydioxanone; a polycarbonate; apolyaminocarbonate; a poly(vinyl pyrrolidone); a poly(ethyl oxazoline);a carboxymethyl cellulose; a hydroxyalkylated cellulose; a polypeptide;a polysaccharide; a carbohydrate; heparan sulfate; chondroitin sulfate;heparin, alginate; and a combination thereof.
 3. The method of claim 2,wherein the thiol compound comprises a polymeric moiety selected fromthe group consisting of polypeptide, poly(lactic acid) (PLA), poly(vinylalcohol) (PVA), and poly(ethylene glycol) (PEG), and a combinationthereof.
 4. The method of claim 1, wherein the ene compound comprises apolymeric moiety selected from the group consisting of poly(lactic acid)(PLA); polyglycolide (PGA); a copolymer of PLA and PGA (PLGA);poly(vinyl alcohol) (PVA); poly(ethylene glycol) (PEG); poly(ethyleneoxide); a poly(ethylene oxide)-co-poly(propylene oxide) block copolymer;a poloxamine; a polyanhydride; a polyorthoester; a poly(hydroxy acids);a polydioxanone; a polycarbonate; a polyaminocarbonate; a poly(vinylpyrrolidone); a poly(ethyl oxazoline); a carboxymethyl cellulose; ahydroxyalkylated cellulose; a polypeptide; a polysaccharide; acarbohydrate; heparan sulfate; chondroitin sulfate; heparin, alginate;and a combination thereof.
 5. The method of claim 4, wherein the enecompound comprises a polymeric moiety selected from the group consistingof polypeptide, poly(lactic acid) (PLA), poly(vinyl alcohol) (PVA), andpoly(ethylene glycol) (PEG), and a combination thereof.
 6. The method ofclaim 1, wherein the molecular weight of the thiol compound is fromabout 30 DA to about 50 kDa.
 7. The method of claim 1, wherein themolecular weight of the ene compound is from about 30 DA to about 50kDa.
 8. The method of claim 1, wherein the ene compound comprises anolefin moiety selected from the group consisting of a vinyl moiety, anacetyl moiety, a vinyl ether moiety, an allyl moiety, an acrylatemoiety, a methacrylate moiety, a maleimide moiety, and a norbornenemoiety.
 9. The method of claim 1, wherein the polymerization reactionmixture further comprises a chemical initiator.
 10. The method of claim1, wherein the radical polymerization reaction is photoinitiated radicalpolymerization reaction.
 11. A biocompatible cross-linked degradablethiol-ene hydrogel polymer of the formula:—[—S—R₁—S—C—C—R₂—C—C—]— wherein R₁ and R₂ are independent linkers, andat least one of R₁ and R₂ is degradable, and wherein at least one of R₁and R₂ comprises a cross-linking moiety; and wherein each of R₁ and R₂independently comprises a polymeric moiety selected from the groupconsisting of poly(lactic acid) (PLA); polyglycolide (PGA); a copolymerof PLA and PGA (PLGA); poly(vinyl alcohol) (PVA); poly(ethylene glycol)(PEG); poly(ethylene oxide); a poly(ethylene oxide)-co-poly(propyleneoxide) block copolymer; a poloxamine; a polyanhydride; a polyorthoester;a poly(hydroxy acids); a polydioxanone; a polycarbonate; apolyaminocarbonate; a poly(vinyl pyrrolidone); a poly(ethyl oxazoline);a carboxymethyl cellulose; a hydroxyalkylated cellulose; a polypeptide;a polysaccharide; a carbohydrate; heparan sulfate; chondroitin sulfate;heparin, alginate; and a combination thereof, and wherein each of the—C—C— portion of Formula I is derived from an olefinic portion of avinyl moiety, a vinyl acetyl moiety, a vinyl ether moiety, an allylmoiety, an acrylate moiety, a methacrylate moiety, a maleimide moiety,or a norbornene moiety.
 12. The biocompatible cross-linked degradablethiol-ene hydrogel polymer of claim 11, wherein each of R₁ and R₂independently comprises a polymeric moiety selected from the groupconsisting of polypeptide, poly(lactic acid) (PLA), poly(vinyl alcohol)(PVA), and poly(ethylene glycol) (PEG), and a combination thereof. 13.The biocompatible cross-linked degradable thiol-ene hydrogel polymer ofclaim 11, wherein the —C—C— portion of Formula I is derived from anolefinic portion of a norbornene moiety.
 14. A biocompatiblecross-linked degradable thiol-ene hydrogel polymer produced by themethod of claim
 1. 15. The biocompatible cross-linked degradablethiol-ene hydrogel polymer of claim 14, wherein the radicalpolymerization reaction is photoinitiated radical polymerizationreaction.